Methods of using low-dose doxepin for the improvement of sleep

ABSTRACT

Methods of preventing early awakenings, and improving sleep efficiency in hours 7 and 8 of a period of sleep, by administration of low doses of doxepin (e.g., 1-6 mg).

RELATED APPLICATIONS

This application is a continuation of application Ser. No. 15/864,440,filed Jan. 8, 2018, which is a continuation of application Ser. No.15/344,710, filed Nov. 7, 2016, now U.S. Pat. No. 9,861,607, which is acontinuation of application Ser. No. 14/804,595, filed Jul. 21, 2015,now U.S. Pat. No. 9,486,437, which is a continuation of application Ser.No. 13/492,559, filed Jun. 8, 2012, now U.S. Pat. No. 9,107,898, whichis a continuation of application Ser. No. 11/804,720, filed May 18,2007, now U.S. Pat. No. 8,513,299, which claims priority under 35 U.S.C.119(e) to United States Provisional Application No. 60/801,824, filedMay 19, 2006; and 60/833,319, filed Jul. 25, 2006; the entire contentsof each of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to the use of low doses of doxepin (e.g.,1-6 milligrams) to improve sleep, including sleep efficiency and earlyawakening in an individual.

BACKGROUND OF THE INVENTION

Sleep is essential for health and quality of life. Insomnia is a growinghealth problem in the United States. It is believed that more than 10-15million people suffer from chronic insomnia and up to an additional 70million people suffer from some form of insomnia each year. Insomnia isa condition characterized by difficulty falling asleep (sleep onset),waking frequently during the night (fragmented sleep), waking too early(premature final awakening), and/or waking up feeling un-refreshed. Inthe National Sleep Foundation's (NSF) Sleep in America Poll 2005, 42% ofsurvey respondents reported that they awoke frequently during the night,22% of adults reported waking too early and not being able to return tosleep and 38% reported waking and feeling un-refreshed.

Sleep maintenance difficulty is the most commonly reported symptom inprimary care patients with chronic insomnia, and is the most commoncomplaint in depressed patients, medically ill populations, especiallythose with pain symptoms, and in the elderly.

Medications commonly used to treat sleep disorders, such as insomnia,include sedative antidepressants, antihistamines, benzodiazepines, andnon-benzodiazepine hypnotics.

Although there have been several advances in pharmaceutical treatmentsfor insomnia, it is often hard to find an ideal drug for treatingparticular forms of insomnia. One common problem is early termination ofsleep or premature final awakening. For example, many individuals maywake prematurely and not fall back asleep, thereby failing to achieve afull night of sleep. Many drugs that are effective in inducing orexpediting sleep initiation do not provide much effect in maintainingsleep, particularly through the eighth and final hour of sleep period.Drugs that are sufficiently powerful to induce a full eight hours sleepoften cause serious hangover effects, i.e., the patient has difficultyawakening and/or feels sedated, sleepy, or disoriented and maydemonstrate impairment of psychomotor function.

In addition to patients having difficulty with early termination ofsleep during the last 60, 90, or 120 minutes of an 8 hour sleep period,other patients have problems with fragmented or disrupted sleep. Inother words, those patients awaken one or more times during that timeperiod, then fall asleep again. Such fragmented sleep patterns detractfrom a feeling of restfulness, and make it less likely that the patientwill enjoy restful sleep.

Both groups of patients would benefit greatly from a drug that addressestheir particular sleep deficiency.

Doxepin is a tricyclic antidepressant that is known to have beneficialeffects in treating insomnia. See, e.g., U.S. Pat. Nos. 5,502,047 and6,211,229. However, prior to the present invention, doxepin was notknown to have particular efficacy in treating premature termination ofsleep at the end of an 8 hour sleep period, nor was it known to beefficacious in treating those patients with disturbed sleep patternsduring the final 60, 90, or 120 minutes of an 8-hour sleep period. Themean half-life of doxepin is 17 hours, and the half-life of its majoractive metabolite, desmethyldoxepin, is 51 hours. Thus, when taken atthe start of a sleep cycle, a majority of the drug or active metaboliteshould still be present in the body at the end of the sleep cycle. As aresult, it would be expected that dosages of doxepin that are sufficientto address premature final awakenings or last-hour sleep efficiency inthe elderly would also cause post-sleep sedation or other undesirableside effects.

The present invention describes the surprising ability of doxepin totreat last-hour sleep efficiency and premature final awakenings inpatients, without untoward side effects.

SUMMARY OF THE INVENTION

Some embodiments provide methods for reducing or preventing earlyawakenings in a patient in need thereof. In some embodiments the methodscan include identifying a patient having a sleep disorder in which, fora given 8 hour period of desired sleep, the patient experiences a sleepperiod that terminates during the final 60 minutes of said period; andadministering to the patient, prior to the sleep period, doxepin, apharmaceutically accept salt thereof, or a prodrug thereof in a dosagebetween 1 milligram (mg) and 6 mg that can be effective to lengthen thesleep period. In some aspects of the embodiment, the patient can beidentified as experiencing a sleep period that terminates during thefinal 45 minutes of said period. In some aspects of the embodiment, thepatient can be identified as experiencing a sleep period that terminatesduring the final 30 minutes of said period. In some embodiments, thesleep period can be lengthened to terminate during or after hour 7 ofsaid period. In some embodiments, the sleep period can be lengthened toterminate during or after hour 7.5 of said period. In some aspects, thepatient can be additionally identified as in need of reducing wake timeafter sleep. In another embodiment, the patient suffers from chronic ornon-chronic insomnia. In yet another embodiment, the patient suffersfrom transient insomnia.

Some embodiments provide methods for decreasing fragmented sleep in the8th hour of a sleep period for a patient. In some embodiments themethods include identifying a patient suffering from fragmented sleepduring the 8th hour of a sleep period; and administering to the patientdoxepin, a pharmaceutically acceptable salt or prodrug thereof in adosage between about 1 mg and 6 mg. In some embodiments, the dosage ofdoxepin can be, for example, about 1 mg, 3 mg or 6 mg. Thus, in oneaspect the dosage of doxepin can be about 1 mg. In one aspect, thedosage of doxepin can be about 3 mg. In one aspect, the dosage ofdoxepin is about 6 mg. In another embodiment, the patient suffers fromchronic or non-chronic insomnia. In yet another embodiment, the patientsuffers from transient insomnia.

Some embodiments provide methods for treating a sleep disorder,comprising identifying a patient suffering from a transient insomniacomprising a sleep deficiency associated with one or more of LPS, WASO,TST, TWT, SE, latency to Stage 2 sleep, WTDS, or WTAS; and administeringto the patient doxepin, a pharmaceutically acceptable salt or prodrugthereof in a dosage between about 0.5 mg and 6 mg. In one embodiment,the dosage of doxepin is about 1 mg, 3 mg or 6 mg. In other embodiments,the dosage of doxepin is about 0.5 mg, 1 mg, 3 mg or 6 mg.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the different parameters that can be analyzed usingpolysomnography.

FIG. 2 is a graph showing the doxepin plasma profile concentration atvarious time points for 1 mg, 3 mg and 6 mg doxepin.

FIG. 3 is a graph showing sleep efficiency (SE) by hour of night inelderly adults after treatment with 1 mg, 3 mg and 6 mg doxepin(per-protocol data).

FIG. 4 is a graph showing SE by hour of night in adults (18-64 yearsold) treated with 1 mg, 3 mg or 6 mg doxepin.

FIG. 5 is a graph showing SE by hour of night in adults treated withplacebo, 3 mg doxepin or 6 mg doxepin.

FIG. 6 is a graph showing SE by hour of night on nights 1, 15 and 29 inadults treated with 3 mg doxepin or 6 mg doxepin.

FIG. 7 is a graph showing SE by Hour of the Night on Night 1: ITTAnalysis Set.

FIG. 8 is a graph showing SE by hour of night in adults with transientinsomnia treated with 6 mg doxepin.

DETAILED DESCRIPTION OF THE INVENTION

Many individuals currently suffer from sleep disorders, such asinsomnia. Some of these individuals with insomnia are subject to shortertotal sleep periods due to premature final awakenings. Also, some ofthese individuals suffer from transient awakenings, particularly duringthe last 1-2 hours of their sleep period. The premature final awakeningsand the transient awakening during the final hours of sleep causes theindividuals to be tired and un-refreshed, and can decrease their overallwell-being and productivity. Thus, there is a need for methods oftreating such individuals to improve sleep efficiency and the totalsleep time.

The present invention relates to methods of using doxepin, for example,low doses of doxepin to improve the sleep of such individuals. Someembodiments relate to methods of using doxepin to prevent or reduce theearly final awakening of an individual. Also, some embodiments relate todecreasing the transient awakenings during the last hours of sleep,preferably in the last hour of a sleep period for an individual.

As mentioned above, various medications are currently approved for thetreatment of sleep disorders, such as insomnia. Many of the approvedmedications have unfavorable side effects. Additionally, the previouslyapproved medications do not effectively manage the sleep experience foran individual taking the medication. For example, the approvedmedications do not improve fragmented sleep for a patient in the finalhours of sleep, especially the last hour of a sleep period. Furthermore,as an example, many of the already approved medications do not reduce orprevent the early final awakening of an individual that is taking themedication. In short, the currently approved medications do notcompletely improve the sleep experience for patients in the final hoursof sleep.

Doxepin HCl is a tricyclic compound currently approved for treatment ofdepression. The recommended daily dose for the treatment of depressionranges from 75 mg to 300 mg. Doxepin, unlike most FDA approved productsfor the treatment of insomnia, is not a Schedule IV controlledsubstance. U.S. Pat. Nos. 5,502,047 and 6,211,229, the entire contentsof which are incorporated herein by reference, describe the use ofdoxepin for the treatment chronic and non-chronic (e.g., transient/shortterm) insomnias at dosages far below those used to treat depression.

Some embodiments of this invention relate to the ability of low-dosedoxepin, pharmaceutically acceptable salts or prodrugs thereof toprevent premature or early final awakenings, and/or to improvefragmented sleep, which can be measured by decrements in sleepefficiency (SE) during the seventh and eighth hours of an eight hourperiod of sleep, by identifying an individual in need of such treatment,and providing a low dose of doxepin, a pharmaceutically acceptable saltthereof, or a prodrug thereof to the individual.

Definitions

As used herein, the term “polysomnography” (PSG) refers a diagnostictest during which a number of physiologic variables are measured andrecorded during sleep. Physiologic sensor leads are placed on thepatient in order to record brain electrical activity, eye and jaw musclemovement, leg muscle movement, airflow, respiratory effort (chest andabdominal excursion), EKG and oxygen saturation Information is gatheredfrom all leads and fed into a computer and outputted as a series ofwaveform tracings which enable the technician to visualize the variouswaveforms, assign a score for the test, and assist in the diagnosticprocess. The primary efficacy variable, wake time during sleep (WTDS)and various secondary efficacy variables are all based on the PSG andare defined as follows.

“Wake Time During Sleep” (WTDS), typically expressed in minutes, is thenumber of wake events (epochs) after the onset of persistent sleep andprior to final awakening, divided by two. Each epoch is defined as a30-second duration on the PSG recording.

“Wake Time After Sleep” (WTAS), typically expressed in minutes, is thenumber of epochs after the final awakening until the end of PSGrecording (i.e., a wake epoch immediately prior to the end of therecording), divided by two. If the patient does not have a wake epochimmediately prior to the end of the recording, then WTAS is zero.

“Wake After Sleep Onset” (WASO) is the sum of WTDS and WTAS.

“Latency to Persistent Sleep” (LPS), typically expressed in minutes, isthe number of epochs from the beginning of the PSG recording(lights-out) to the start of the first 20 consecutive non-wake epochs,divided by two.

“Total Sleep Time” (TST), typically expressed in minutes, is the numberof non-wake epochs from the beginning of the PSG recording to the end ofthe recording, divided by two.

“Sleep Efficiency” (SE) is the TST divided by the time in bed (8 hours),multiplied by 100 and expressed as a percentage. This also can bedivided into SE for each third-of-the-night of sleep, reflecting the SEfor each 160 minute time interval across the night. Finally, SE can bemeasured for individual hours during the night or sleep period, forexample the final hour of the sleep period.

The term “fragmented sleep” can refer to interrupted sleep over ameasurement period or sleep period, for example the time a patient isawake during period of measurement. Fragmentation can occur as a resultof multiple awakenings or one or more awakenings of a long duration.

The term “prodrug” refers to an agent that is converted into the activedrug in vivo. Prodrugs are often useful because, in some situations,they may be easier to administer than the active drug. They may, forinstance, be bioavailable by oral administration whereas the active drugis not. The prodrug may also have improved solubility in pharmaceuticalcompositions over the active drug. An example, without limitation, of aprodrug would be a compound of the present invention which isadministered as an ester (the “prodrug”) to facilitate transmittalacross a cell membrane where water solubility is detrimental to mobilitybut which then is metabolically hydrolyzed to the carboxylic acid, theactive entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety.

The term “pharmaceutically acceptable salt” refers to an ionic form of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. Pharmaceutical salts can be obtained byreacting a compound of the invention with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. Pharmaceuticalsalts can also be obtained by reacting a compound of the invention witha base to form a salt such as an ammonium salt, an alkali metal salt,such as a sodium or a potassium salt, an alkaline earth metal salt, suchas a calcium or a magnesium salt, a salt of organic bases such asdicyclohexylamine, N-methyl-D-glutamine, tris(hydroxymethyl)methylamine,and salts with amino acids such as arginine, lysine, and the like.

The term “low dose” can refer to a daily dose range of between about 0.5and 6 mg. In some embodiments, daily dosages of low dose doxepin can beabout 1, 2, 3, 4, 5 or 6 mg. These dosages have reduced side effects,are surprisingly effective, and have a relatively rapid onset. In oneembodiment, an initial daily dosage of about 1 mg can be given. If thedesired improvement in sleep is not achieved, then the dosage may beincrementally increased until the desired dosage is achieved or until amaximum desired dosage is reached which can be, for example, 2 mg, 3 mg,4 mg, 5 mg or 6 mg. It should be noted that other dosages of doxepin canbe used in the embodiments described herein. For example, the dosage canbe about 0.5 to about 10 mg.

Compounds

Doxepin:

Doxepin HCl is a tricyclic compound currently approved and available fortreatment of depression and anxiety. Doxepin has the followingstructure:

For all compounds disclosed herein, unless otherwise indicated, where acarbon-carbon double bond is depicted, both the cis and transstereoisomers, as well as mixtures thereof are encompassed.

Doxepin belongs to a class of psychotherapeutic agents known asdibenzoxepin tricyclic compounds, and is currently approved andprescribed for use as an antidepressant to treat depression and anxiety.Doxepin has a well-established safety profile, having been prescribedfor over 35 years.

Doxepin, unlike most FDA approved products for the treatment ofinsomnia, is not a Schedule IV controlled substance. U.S. Pat. Nos.5,502,047 and 6,211,229, the entire contents of which are incorporatedherein by reference, describe the use of doxepin for the treatmentchronic and non-chronic (e.g., transient/short term) insomnias atdosages far below those used to treat depression.

It is contemplated that doxepin for use in the methods described hereincan be obtained from any suitable source or made by any suitable method.As mentioned, doxepin is approved and available in higher doses (75-300milligrams) for the treatment of depression and anxiety. Doxepin HCl isavailable commercially and may be obtained in capsule form from a numberof sources. Doxepin is marketed under the commercial name SINEQUAN® andin generic form, and can be obtained in the United States generally frompharmacies in capsule form in amounts of 10, 25, 50, 75, 100 and 150 mgdosage, and in liquid concentrate form at 10 mg/mL. Doxepin HCl can beobtained from Plantex Ltd. Chemical Industries (Hakadar Street,Industrial Zone, P.O. Box 160, Netanya 42101, Israel), Sifavitor S.p.A.(Via Livelli 1-Frazione, Mairano, Italy), or from Dipharma S.p.A. (20021Baranzate di Bollate, Milano, Italy). Also, doxepin is commerciallyavailable from PharmacyRx (NZ) (2820 1^(st) Avenue, Castlegar, B.C.,Canada) in capsule form in amounts of 10, 25, 50, 75, 100 and 150 mg.Furthermore, Doxepin HCl is available in capsule form in amounts of 10,25, 50, 75, 100 and 150 mg and in a 10 mg/ml liquid concentrate from CVSOnline Pharmacy Store (CVS.com).

Also, doxepin can be prepared according to the method described in U.S.Pat. No. 3,438,981, which is incorporated herein by reference in itsentirety. It should be noted and understood that although many of theembodiments described herein specifically refer to “doxepin,” otherdoxepin-related compounds can also be used, including, for example,pharmaceutically acceptable salts, prodrugs, metabolites, in-situ saltsof doxepin formed after administration, and solid state forms, includingpolymorphs and hydrates.

Metabolites:

In addition, doxepin metabolites can be prepared and used. By way ofillustration, some examples of metabolites of doxepin can include, butare not limited to, desmethyldoxepin, hydroxydoxepin,hydroxyl-N-desmethyldoxepin, doxepin N-oxide,N-acetyl-N-desmethyldoxepin, N-desmethyl-N-formyldoxepin, quaternaryammonium-linked glucuronide, 2-O-glucuronyldoxepin, didesmethyldoxepin,3-O-glucuronyldoxepin, or N-acetyldidesmethyldoxepin. The metabolites ofdoxepin can be obtained or made by any suitable method, including themethods described above for doxepin.

Desmethyldoxepin has the following structure:

Desmethyldoxepin is commercially available as a forensic standard. Forexample, it can be obtained from Cambridge Isotope Laboratories, Inc.(50 Frontage Road, Andover, Mass.). Desmethyldoxepin for use in themethods discussed herein can be prepared by any suitable procedure. Forexample, desmethyldoxepin can be prepared from 3-methylaminopropyltriphenylphosphonium bromide hydrobromide and6,11-dihydrodibenz(b,e)oxepin-11-one according to the method taught inU.S. Pat. No. 3,509,175, which is incorporated herein by reference inits entirety.

Hydroxydoxepin has the following structure:

2-Hydroxydoxepin can be prepared by any suitable method, including astaught by Shu et al. (Drug Metabolism and Disposition (1990)18:735-741), which is incorporated herein by reference in its entirety.

Hydroxyl-N-desmethyldoxepin has the following structure:

2-Hydroxy-N-desmethyldoxepin can be prepared any suitable method.

Doxepin N-oxide has the following structure:

Doxepin N-oxide can be prepared by any suitable method. For example,doxepin N-oxide can be prepared as taught by Hobbs (Biochem Pharmacol(1969) 18:1941-1954), which is hereby incorporated by reference in itsentirety.

N-acetyl-N-desmethyldoxepin has the following structure:

N-acetyl-N-desmethyldoxepin can be prepared by any suitable means. Forexample, (E)-N-acetyl-N-desmethyldoxepin has been produced infilamentous fungus incubated with doxepin as taught by Moody et al.(Drug Metabolism and Disposition (1999) 27:1157-1164), herebyincorporated by reference in its entirety.

N-desmethyl-N-formyldoxepin has the following structure:

N-desmethyl-N-formyldoxepin can be prepared by any suitable means. Forexample, (E)-N-desmethyl-N-formyldoxepin has been produced infilamentous fungus incubated with doxepin as taught by Moody et al.(Drug Metabolism and Disposition (1999) 27:1157-1164), herebyincorporated by reference in its entirety.

N-acetyldidesmethyldoxepin has the following structure:

N-acetyldidesmethyldoxepin can be prepared by any suitable means. Forexample, (E)-N-acetyldidesmethyldoxepin has been produced in filamentousfungus incubated with doxepin as taught by Moody et al. (Drug Metabolismand Disposition (1999) 27:1157-1164), hereby incorporated by referencein its entirety.

Didesmethyldoxepin has the following structure:

Didesmethyldoxepin can be prepared by any suitable means. For example,(Z)- and (E)-didesmethyldoxepin have been isolated from plasma andcerebrospinal fluid of depressed patients taking doxepin, as taught byDeuschle et al. (Psychopharmacology (1997) 131:19-22), herebyincorporated by reference in its entirety.

3-O-glucuronyldoxepin has the following structure:

3-O-glucuronyldoxepin can be prepared by any suitable means. Forexample, (E)-3-O-glucuronyldoxepin has been isolated from the bile ofrats given doxepin, as described by Shu et al. (Drug Metabolism andDisposition (1990) 18:1096-1099), hereby incorporated by reference inits entirety.

2-O-glucuronyldoxepin has the following structure:

2-O-glucuronyldoxepin can be prepared by any suitable means. Forexample, (E)-2-O-glucuronyldoxepin has been isolated from the bile ofrats given doxepin, and also in the urine of humans given doxepin, asdescribed by Shu et al. (Drug Metabolism and Disposition (1990)18:1096-1099), hereby incorporated by reference in its entirety.

Quaternary ammonium-linked glucuronide of doxepin (doxepinN⁺-glucuronide) has the following structure:

N⁺-glucuronide can be obtained by any suitable means. For example,doxepin N⁺-glucuronide can be prepared as taught by Luo et al. (DrugMetabolism and Disposition, (1991) 19:722-724), hereby incorporated byreference in its entirety.

Pharmaceutically Acceptable Salts:

As mentioned above, the methods and other embodiments described hereincan utilize any suitable pharmaceutically acceptable salt or prodrug ofdoxepin, or salts or prodrugs of doxepin metabolites. Therefore, thesubstitution or use in combination of salts and prodrugs is specificallycontemplated in the embodiments described herein. The pharmaceuticallyacceptable salts and prodrugs can be made by any suitable method.

The term “pharmaceutically acceptable salt” refers to an ionic form of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. Pharmaceutical salts can be obtained byreacting a compound of the invention with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. Pharmaceuticalsalts can also be obtained by reacting a compound of the invention witha base to form a salt such as an ammonium salt, an alkali metal salt,such as a sodium or a potassium salt, an alkaline earth metal salt, suchas a calcium or a magnesium salt, a salt of organic bases such asdicyclohexylamine, N-methyl-D-glutamine, tris(hydroxymethyl)methylamine,and salts with amino acids such as arginine, lysine, and the like.Pharmaceutically acceptable salts are more fully described in thefollowing paragraph.

The acids that can be used to prepare pharmaceutically acceptable acidaddition salts include, for example, those that form non-toxic acidaddition salts, i.e., salts containing pharmacologically acceptableanions, such as the acetate, benzenesulfonate, benzoate, bicarbonate,bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate,carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate,dislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate,gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate(embonate), palmitate, pantothenate, phospate/diphosphate,polygalacturonate, salicylate, stearate, subacetate, succinate, tannate,tartrate, teoclate, tosylate, triethiodode, and valerate salts.

The bases that can be used to prepare pharmaceutically acceptable baseaddition salts include, for example, those that form non-toxic baseaddition salts, i.e., base salts formed with metals or amines, such asalkali and alkaline earth metals or organic amines. Non-limitingexamples of metals used as cations include sodium, potassium, magnesium,calcium, and the like. Also included are heavy metal salts such as forexample silver, zinc, cobalt, and cerium. Non-limiting examples ofsuitable amines include N,N′-dibenzylethylenediamine, chloroprocaine,choline, diethanolamine, ethylenediamene, N-methylglucamine, andprocaine.

Prodrugs:

The term “prodrug” refers to an agent that is converted into the activedrug in vivo. Prodrugs are often useful because, in some situations,they can be easier to administer than the active drug. They can, forinstance, be bioavailable by oral administration whereas the active drugis not. The prodrug may also have improved solubility in pharmaceuticalcompositions over the active drug. An example, without limitation, of aprodrug would be a compound of the present invention which isadministered as an ester (the “prodrug”) to facilitate transmittalacross a cell membrane where water solubility is detrimental to mobilitybut which then is metabolically hydrolyzed to the carboxylic acid, theactive entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety. Examples of prodrug groups can be found in,for example, T. Higuchi and V. Stella, in “Pro-drugs as Novel DeliverySystems,” Vol. 14, A.C.S. Symposium Series, American Chemical Society(1975); H. Bundgaard, “Design of Prodrugs,” Elsevier Science, 1985; and“Bioreversible Carriers in Drug Design: Theory and Application,” editedby E. B. Roche, Pergamon Press: New York, 14-21 (1987), each of which ishereby incorporated by reference in its entirety.

Methods of Using Low Dose Doxepin

Some embodiments relate to methods for reducing or preventing prematureawakening in a patient in need thereof. The methods can include the stepof identifying a patient having a sleep disorder in which, for a givensleep period of desired sleep, for example an 8 hour period, the patientexperiences a sleep period that terminates prior to or during the final60 minutes of the period; and administering to the patient a dosage ofdoxepin that is effective to lengthen the sleep period, preferablybetween about 1 and 6 mg. In some aspects the patient can experience asleep period that terminates within the final 60 minutes, 45 minutes, 30minutes or 15 minutes. In other aspects the sleep period can terminateeven earlier, for example, during the final 90 minutes, the final 120minutes, or longer. In some aspects, the sleep period may be lengthenedby administering low dose doxepin to extend the sleep period toterminate during or after hour 7 (e.g., hour 7.5) of an 8 hour period ofsleep. Also, the patients can be identified as being in need of reducedwake time during (or after) sleep.

Further, some embodiments relate to methods for improving fragmentedsleep in the final hours of a sleep period for a patient, preferablyduring the final hour or the 8^(th) hour of sleep. The methods caninclude, for example, the steps of identifying a patient suffering fromor experiencing fragmented sleep during last hour or hours of a sleepperiod, and administering to the patient doxepin in a dosage betweenabout 1 mg and 6 mg. Preferably, the methods can be used to reduce orimprove fragmented sleep during the 8th hour of a sleep period. In someaspects the dosage of doxepin can be about 1 mg, 3 mg or 6 mg.

Some embodiments relate to methods of using low dose doxepin to decreaseWTAS in an individual who is prone to early awakenings. An individualwith such a need can be identified, and low doses of doxepin can beadministered to the individual, for example, prior to the sleep period.

The methods described herein can be used to treat individuals sufferingfrom a sleep disorder, such as insomnia. The individual can suffer froma chronic insomnia or a non-chronic insomnia. For chronic (e.g., greaterthan 3-4 weeks) or non-chronic insomnias, a patient may suffer fromdifficulties in sleep onset, sleep maintenance (interruption of sleepduring the night by periods of wakefulness), sleep duration, sleepefficiency, premature early-morning awakening, or a combination thereof.Also, the insomnia may be attributable to the concurrent use of othermedication, for example. The non-chronic insomnia can be, for example, ashort term insomnia or a transient insomnia. The chronic or non-chronicinsomnia can be a primary insomnia or an insomnia that is secondary orattributable to another condition, for example a disease such asdepression or chronic fatigue syndrome. In some aspects, the patient canbe one that is not suffering from an insomnia that is a component of adisease, or a patient can be treated that is otherwise healthy. Aspreviously mentioned, the chronic or non-chronic insomnia can be aprimary insomnia, that is, one that is not attributable to anothermental disorder, a general medical condition, or a substance. In manycases, such conditions may be associated with a chronic insomnia and caninclude, but are not limited to, insomnia attributable to a diagnosableDSM-IV disorder, a disorder such as anxiety or depression, or adisturbance of the physiological sleep-wake system. In some aspects theinsomnia can be non-chronic, or of short duration (e.g., less than 3-4weeks). Examples of causes of such insomnia may be extrinsic orintrinsic and include, but are not limited to environmental sleepdisorders as defined by the International Classification of SleepDisorders (ICSD) such as inadequate sleep hygiene, altitude insomnia oradjustment sleep disorder (e.g., bereavement). Also, short-term insomniamay also be caused by disturbances such as shift-work sleep disorder.

Administration of Doxepin

In performing the methods, doxepin, a pharmaceutically acceptable saltof doxepin, or prodrug of doxepin can be administered using any suitableroute or method of delivery. Also, doxepin, a pharmaceuticallyacceptable salt or a prodrug thereof can be included and administered ina composition.

Suitable routes of administration include oral, buccal, sublingual,transdermal, rectal, topical, transmucosal, or intestinaladministration; parenteral delivery, including intramuscular,subcutaneous, intravenous, intramedullary injections, as well asintrathecal, direct intraventricular, intraperitoneal, intranasal, orintraocular injections.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Administration though oralpathways can be accomplished, for example, using a capsule, a tablet, agranule, a spray, a syrup, a liquid, powder, granules, pastes (e.g., forapplication to the tongue). Oral administration can be accomplishedusing fast-melt formulations, for example. Pharmaceutical preparationsfor oral use can be obtained by mixing one or more solid excipient withpharmaceutical combination of the invention, optionally grinding theresulting mixture, and processing the mixture of granules, after addingsuitable auxiliaries, if desired, to obtain tablets or dragee cores.Suitable excipients are, in particular, fillers such as sugars,including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents may beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate.

Pharmaceutical preparations which can be used orally, includingsublingually, include for example, liquid solutions, powders, andsuspensions in bulk or unit dosage forms. Also, the oral formulationscan include, for example, pills, tablets, granules, sprays, syrups,pastes, powders, boluses, pre-measured ampules or syringes, push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

For buccal administration, the compositions may take any suitable form,for example, tablets or lozenges.

For topical administration, the compounds may be formulated foradministration to the epidermis as ointments, gels, creams, pastes,salves, gels, creams or lotions, or as a transdermal patch. Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents. Lotionsmay be formulated with an aqueous or oily base and will in general alsocontaining one or more emulsifying agents, stabilizing agents,dispersing agents, suspending agents, thickening agents, or coloringagents.

For injection, the agents of the invention may be formulated in aqueoussolutions, preferably in physiologically compatible buffers such asHanks's solution, Ringer's solution, or physiological saline buffer. Fortransmucosal administration, penetrants appropriate to the barrier to bepermeated are used in the formulation. Such penetrants are generallyknown in the art.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebulizer, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, orother suitable gas. In the case of a pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, e.g., gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

In addition, any of the compounds and compositions described herein canalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt. Furthermore, any of the compounds andcompositions described herein also can be formulated as a fast-meltpreparation. The compounds and compositions can also be formulated andadministered as a drip, a suppository, a salve, an ointment, anabsorbable material such a transdermal patch, or the like.

One can also administer the compounds of the invention in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can be foundin the incorporated materials in Remington: The Science and Practice ofPharmacy (20^(th) ed, Lippincott Williams & Wilkens Publishers (2003)),which is incorporated herein by reference in its entirety.

A variety of techniques for formulation and administration can be foundin Remington: The Science and Practice of Pharmacy (20^(th) ed,Lippincott Williams & Wilkens Publishers (2003)), which is incorporatedherein by reference in its entirety.

Compositions

As mentioned above, doxepin, pharmaceutically acceptable salts, and/orprodrugs of the same can be used alone or in combination with othersubstances, such as for example, other insomnia or sleep medications, orwith other medications that treat a primary illness. The doxepin aloneor in combination can be included as part of a composition. Thecompounds and compositions can include any suitable form of the compoundfor pharmaceutical delivery, as discussed in further detail herein.

The compositions and formulations disclosed herein also can include oneor more pharmaceutically acceptable carrier materials or excipients.Such compositions can be prepared for storage and for subsequentadministration. Acceptable carriers or diluents for therapeutic use arewell known in the pharmaceutical art, and are described, for example, inthe incorporated material of Remington: The Science and Practice ofPharmacy (20^(th) ed, Lippincott Williams & Wilkens Publishers (2003)),which is incorporated herein by reference in its entirety. The term“carrier” material or “excipient” herein can mean any substance, notitself a therapeutic agent, used as a carrier and/or diluent and/oradjuvant, or vehicle for delivery of a therapeutic agent to a subject oradded to a pharmaceutical composition to improve its handling or storageproperties or to permit or facilitate formation of a dose unit of thecomposition into a discrete article such as a capsule or tablet suitablefor oral administration. Excipients can include, by way of illustrationand not limitation, diluents, disintegrants, binding agents, adhesives,wetting agents, polymers, lubricants, glidants, substances added to maskor counteract a disagreeable taste or odor, flavors, dyes, fragrances,and substances added to improve appearance of the composition.Acceptable excipients include lactose, sucrose, starch powder, maizestarch or derivatives thereof, cellulose esters of alkanoic acids,cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinyl-pyrrolidone,and/or polyvinyl alcohol, saline, dextrose, mannitol, lactose, lecithin,albumin, sodium glutamate, cysteine hydrochloride, and the like.Examples of suitable excipients for soft gelatin capsules includevegetable oils, waxes, fats, semisolid and liquid polyols. Suitableexcipients for the preparation of solutions and syrups include, withoutlimitation, water, polyols, sucrose, invert sugar and glucose. Suitableexcipients for injectable solutions include, without limitation, water,alcohols, polyols, glycerol, and vegetable oils. The pharmaceuticalcompositions can additionally include preservatives, solubilizers,stabilizers, wetting agents, emulsifiers, sweeteners, colorants,flavorings, buffers, coating agents, or antioxidants. Sterilecompositions for injection can be formulated according to conventionalpharmaceutical practice as described in the incorporated material inRemington: The Science and Practice of Pharmacy (20^(th) ed, LippincottWilliams & Wilkens Publishers (2003)). For example, dissolution orsuspension of the active compound in a vehicle such as water ornaturally occurring vegetable oil like sesame, peanut, or cottonseed oilor a synthetic fatty vehicle like ethyl oleate or the like may bedesired. Buffers, preservatives, antioxidants and the like can beincorporated according to accepted pharmaceutical practice. The compoundcan also be made in microencapsulated form. In addition, if desired, theinjectable pharmaceutical compositions may contain minor amounts ofnontoxic auxiliary substances, such as wetting agents, pH bufferingagents, and the like. If desired, absorption enhancing preparations (forexample, liposomes), can be utilized.

The compositions and formulations can include any other agents thatprovide improved transfer, delivery, tolerance, and the like. Thesecompositions and formulations can include, for example, powders, pastes,ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic)containing vesicles (such as Lipofectin™), DNA conjugates, anhydrousabsorption pastes, oil-in-water and water-in-oil emulsions, emulsionscarbowax (polyethylene glycols of various molecular weights), semi-solidgels, and semi-solid mixtures containing carbowax. Any of the foregoingmixtures may be appropriate in treatments and therapies in accordancewith the present invention, provided that the active ingredient in theformulation is not inactivated by the formulation and the formulation isphysiologically compatible and tolerable with the route ofadministration. See also Baldrick P. “Pharmaceutical excipientdevelopment: the need for preclinical guidance.” Regul. Toxicol.Pharmacol. 32(2):210-8 (2000), Charman W N “Lipids, lipophilic drugs,and oral drug delivery-some emerging concepts.” J Pharm Sci0.89(8):967-78 (2000), Powell et al. “Compendium of excipients forparenteral formulations” PDA J Pharm Sci Technol. 52:238-311 (1998) andthe citations therein for additional information related toformulations, excipients and carriers well known to pharmaceuticalchemists.

One can also administer the compounds of the invention in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can be foundin the incorporated materials in Remington: The Science and Practice ofPharmacy (20^(th) ed, Lippincott Williams & Wilkens Publishers (2003)).

Dosage

As mentioned above, in some embodiments the preferable dosage can bebetween about 1 mg and 6 mg. Preferably, the dosage can be about 0.5 mg,1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg or about 6 mg. Itshould be noted that in some embodiments the dosage can be between about0.01 mg and 20 mg or between about 0.5 mg and 10 mg. Further, the dosagecan be about 7 mg, about 8 mg, about 9 mg, or about 10 mg.

The selected dosage level can depend upon, for example, the route ofadministration, the severity of the condition being treated, and thecondition and prior medical history of the patient being treated.However, it is within the skill of the art to start doses of thecompound at levels lower than required to achieve the desiredtherapeutic effect and to gradually increase the dosage until thedesired effect is achieved. It will be understood, however, that thespecific dose level for any particular patient can depend upon a varietyof factors including the genetic makeup, body weight, general health,diet, time and route of administration, combination with other drugs andthe particular condition being treated, and its severity. For thetreatment of insomnia, preferably one dose is administered prior tobedtime.

The selected dosage can also be determined by targeting a mean plasmaconcentration profile that has been associated with improvement in oneor more PSG sleep variables including LPS, WASO, TST, SE, WTDS, or WTAS(FIG. 1). Examples of such plasma concentration profiles are shown inFIG. 2. The target plasma concentration profile may be achieved by anysuitable route of administration including oral, buccal, sublingual,transdermal, rectal, topical, transmucosal, or intestinaladministration; parenteral delivery, including intramuscular,subcutaneous, intravenous, intramedullary injections, as well asintrathecal, direct intraventricular, intraperitoneal, intranasal, orintraocular injections using any suitable formulation.

EXAMPLES Example 1

Doxepin is prepared by the following method.

(a) A Grignard compound is prepared in the conventional manner from 4.8g (0.2 gram-atom) magnesium in 100 mL ether and 30 g (34 ml)(3-chloropropyl)-tertbutyl ether and 16.40 grams (0.078 mol)6,11-dihydrodibenzo-[b,e]-oxepine-11-one dissolved in 100 mL ether isadded in dropwise fashion so that the contents of the flask boillightly. The mixture is heated for 1 hour with agitation in a refluxcondenser to complete the reaction and then it is decomposed withammonium chloride solution. The product which is obtained by separating,drying and eliminating the solvent produced, when the ether residue(24.0 g) is extracted with ligroin, amounts to 20.3 g (80.0% of theory)of 11-(3-tertbutoxypropyl)-11-hydroxy-6,11-dihydrodibenzo-[b,e]-oxepine,having a melting point of 124-126° C. The (3-chloropropyl)-tertbutylether is thereafter obtained in the following manner: 19 g (0.2 mol)1-chloropropanol-(3), 50 mL liquid isobutylene and 0.5 mL concentratedsulfuric acid are permitted to stand for 24 hours in an autoclave, thenare poured into excess sodium bicarbonate solution and extracted withether. The ether solution is dried with calcium chloride and distilled.23.6 grams of (3-chloropropyl)-tertbutyl ether having a boiling point of150-156° C. (78% of theory) are recovered.

(b) 30.8 grams of the11-(3-tertbutoxypropyl)-11-hydroxy-6,11-dihydrodibenzo-[b,e]-oxepineobtained according to (a) above and 150 ml absolute alcoholichydrochloric acid are heated for 1 hour at ebullition. After removingthe solvent by evaporation, the residue is crystallized with ligroin,21.0 grams (88.5% of theory) of11-(3-hydroxypropylidene)-6,11-dihydrodibenzo-[b,e]-oxepine having amelting point of 108-111° C. were obtained. After recrystallization fromacetic acid ester, the compound melts at 112-114° C.

(c) 5.0 ml thionyl chloride dissolved in 5 mL benzene is added dropwiseat room temperature to 12.6 g (0.05 mol) of the11-(3-hydroxypropylidene)-6,11-dihydrodibenzo-[b,e]-oxepine obtained inpart (b) above. After 1 hour of standing, the contents of the flask areheated at ebullition for 2 hours. The volatile components are thereafterremoved and the remainder distilled using high vacuum. The yield amountsto 10.6 g (78.5% of theory) of11-(3-chloropropylidene)-6,11-dihydrodibenzo-[b,e]-oxepine having aB.P.0.1 169-172° C., a melting point of 106-111° C. Afterrecrystallization from 20 ml of acetic acid ester, 9.1 g (67.5% oftheory) of pure product having a melting point of 113-115° C. isobtained. The crude product can however be used quite easily for furtherprocessing.

(d) 5.4 g (0.02 mol) of the11-(3-chloropropylidene)-6,11-dihydrodibenzo-[b,e]-oxepine, preparedaccording to (c) above, in 20 mL tetrahydrofuran and 5.5 g (0.12 mol)dimethylamine in 20 mL ethanol is heated together for 3 hours using aglass autoclave and a temperature of 95-100° C. (boiling water bath).Water and 6 N hydrochloric acid are added to the contents of theautoclave and the mixture is extracted with ether. The separated,aqueous-acid components are then made alkaline with dilute caustic sodasolution, and the oil thereby separated is taken up in ether. The etherresidue, after distillation in a high vacuum, produces 4.1 g (73.5% oftheory) of11-(3-dimethylamino-propylidene)-6,11-dihydrodibenzo-[b,e]-oxepine,having a B.P._(0.1) 147-150° C. The melting point of the hydrochlorideis 182-184° C. (recrystallized from isopropanol).

Example 2 Preparation of Desmethyldoxepin

Desmethyldoxepin is prepared according to the following method.Anhydrous 3-methylaminopropyltriphenylphosphonium bromide hydrobromide(1530 g) prepared as in U.S. Pat. No. 3,509,175, is suspended in 4.5 Ldry tetrahydrofuran and 6.0 moles of butyl lithium in heptane is addedduring 1 hour. After an additional 30 minutes, 483 g of6,11-dihydrodibenz[b,e]oxepin-11-one, is added to the deep red solutionand the reaction is maintained at reflux for 10 hours. Water, 500 mL, isadded at room temperature and the solvent is removed in vacuo. The cruderesidue is treated with 10% hydrochloric acid until acidic (pH 2) andthen 1.5 L benzene is added. After stirring, the mixture separates intothree phases (an insoluble hydrochloride salt product phase, an aqueousphase and an organic phase). The benzene layer is removed by decantationand the remaining mixture is rendered basic with 10% sodium hydroxidesolution and is extracted with 3×1500 mL portions of benzene. Thebenzene extracts are washed, then dried with anhydrous sodium sulfateand concentrated in a vacuum leaving a solid residue ofdesmethyldoxepin.

Example 3 Preparation of (E)-Desmethyldoxepin

(E)-Desmethyldoxepin is prepared from doxepin hydrochloride as follows.Doxepin hydrochloride (E/Z=85/15) (55.0 g, 0.174 mol) is dissolved in600 mL H2O, made basic with 6M NaOH, and extracted with CHCl3 (3×600mL). The CHCl3 extracts are combined, dried over Na2SO4, and solventremoved in vacuo. The resulting oil is dissolved in 250 mL EtOH, then21.15 g (0.182 mol) of maleic acid dissolved in 100 mL EtOH is addedslowly, with stirring, followed by an additional 350 mL EtOH. Theresulting cloudy solution is refluxed until it becomes clear, thenallowed to stand overnight at room temperature; the resulting crystalsare isolated by vacuum filtration. Additional recrystallization fromEtOH yields a white crystalline product ((E)-Doxepin maleate) with anE/Z ratio of 98/2. (E)-Doxepin maleate (2.50 g, 6.32 mmol) is thenpartially dissolved in 60 mL H2O, made basic with 6M NaOH, and extractedwith CHCl3 (3×60 mL). The CHCl3 extracts are combined, washed with 60 mLbrine, dried over Na2SO4, and solvent removed in vacuo. The resultingoil is re-dissolved in 10 mL CHCl3, 1.8 mL (13 mmol) of triethylamineadded, 1.8 mL (13 mmol) of 2,2,2-trichloroethylchloro-formate added, andreaction stirred under N2 for 3.5 hours. The completed reaction is thendiluted with 140 mL Et2O, washed successively with 0.5M HCl (2×140 mL),H2O (140 mL), and brine (140 mL), then dried over MgO4 and solventremoved in vacuo. Resulting material is further purified by silica gelcolumn chromatography, eluting with EtOAc/Hex (20/80), to afford 1.48 g(3.36 mmol) of the desired product as a clear oil. The N-protected(E)-desmethyldoxepin intermediate (1.44 g, 3.27 mmol) is then dissolvedin 12 mL THF, 2.88 g of zinc powder added, 2.3 mL of 1M sodium phosphate(pH=5.5) added, and reaction stirred for 17 hours. The reaction mixtureis then vacuum filtered, filtrate solvent removed in vacuo, andresulting residue purified by silica gel column chromatography, elutingwith THF/MeOH/NH4OH (85/15/0.4), then THF/MeOH/NH4OH (75/25/0.4), toafford 744 mg (2.80 mmol) of the desired product as a pale yellow solid.

Example 4 Preparation of (Z)-Desmethyl Doxepin

(Z)-Desmethyldoxepin is prepared from doxepin hydrochloride as follows.Doxepin hydrochloride (E/Z=85/15) (100 g, 0.317 mol) is dissolved in 800mL H2O, made basic with 6M NaOH, and extracted with CHCl3 (3×800 mL).The CHCl3 extracts are combined, dried over Na2SO4, and solvent removedin vacuo. The resulting oil is dissolved in 700 mL EtOH, then 36.7 g(0.317 mol) of maleic acid dissolved in 600 mL EtOH is added slowly,with stirring. The resulting cloudy solution is refluxed until clear,then allowed to stand overnight at room temperature. Crystals areisolated by vacuum filtration and the mother liquor saved. Crystals arerecrystallized two additional times as above, and the three motherliquors saved and combined and solvent removed in vacuo.Recrystallization of mother liquor material from refluxing EtOHeventually affords 24 g of a mother liquor product which is 65% Z isomerin composition. Recrystallization of this material from 450 mL EtOHgives crystals (9.1 g) which are 80% Z isomer. This material isrecrystallized from 170 mL CHCl3/CCl4 (50/50) at 4° C., yielding 7.65 gof crystalline material which is 87% Z isomer in composition. Threeadditional recrystallizations from CHCl3/CCl4 eventually affords 5.12 g(12.9 mmol) of the desired product ((Z)-Doxepin maleate) with an E/Zratio of 4/96; melting point: 162-163° C. (Z)-Doxepin maleate (1.00 g,2.53 mmol) is then partially dissolved in 35 mL H2O, made basic with 6MNaOH, and extracted with CHCl3 (3×35 mL). The CHCl3 extracts arecombined, washed with 35 mL brine, dried over Na2SO4, and solventremoved in vacuo. The resulting oil is re-dissolved in 4 mL CHCl3, 0.65mL (4.7 mmol) of triethylamine added, 0.65 mL (4.7 mmol) of2,2,2-trichloroethyl-chloroformate added, and reaction stirred under N2for 3.5 hours. The completed reaction is then diluted with 50 mL Et2O,washed successively with 0.5M HCl (2×50 mL), H2O (50 mL), and brine (50mL), then dried over MgO4 and solvent removed in vacuo. Resultingmaterial is further purified by silica gel column chromatography,eluting with EtOAc/Hex (20/80), to afford 710 mg (1.61 mmol) of thedesired product as a clear oil. The N-protected (Z)-desmethyldoxepin(679 mg, 1.54 mmol) is then dissolved in 5.7 mL THF, 1.36 g of zincpowder added, 1.1 mL of 1M sodium phosphate (pH=5.5) added, and reactionstirred for 17 hours. The reaction mixture is then vacuum filtered,filtrate solvent removed in vacuo, and resulting residue purified bysilica gel column chromatography, eluting with THF/MeOH/NH4OH(85/15/0.4), then THF/MeOH/NH4OH (82/18/0.4), to afford 364 mg (1.37mmol) of the desired product as a pale yellow solid.

Example 5 Preparation of(Z)-2-Hydroxy-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin

A mixture of2-methoxy-11-(3-dimethylaminopropyl)-6,11-dihydrodibenzo[b,e]oxepin (165mg, 0.005 mol) with glacial acetic acid (0.2 ml) and hydriodic acid (0.2mL, 57%) was stirred and heated for 5 hr at 90° C. The product was thenextracted and purified by pouring into ice water (25 mL), made alkalinewith sodium hydroxide (2N) and extracted with ether (2×10 mL). Theaqueous layer was then adjusted to pH 6.8 with hydrochloric acid (6N).The mixture was then brought to pH 7 by the addition of sodiumbicarbonate solution (5%) and extracted with chloroform (2×10 mL). Theextract was dried over anhydrous sodium sulfate and evaporated in vacuoto give a yellowish solid. The crude reaction product was purified bypreparative TLC (chloroform/toluene/methanol/ammonia, 4:3:2:1, v/v).

Example 6 Preparation of(E)-2-Hydroxy-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin

A mixture of(Z)-2-Hydroxy-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin(2.5 mg, 8.5×10⁻⁶ mol) was dissolved in a mixture of hydrochloric acid(1 mL) and methanol (9 mL) and heated at 140° C. (oil bath) for 4 hr.The product was isolated by means of HPLC and evaporation of solvents.

Example 7 Preparation of(Z)-2-Hydroxy-11-(3-methylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin

A mixture of2-methoxy-11-(3-methylaminopropyl)-6,11-dihydrodibenzo[b,e]oxepin (0.005mol) with glacial acetic acid (0.2 ml) and hydriodic acid (0.2 ml, 57%)is stirred and heated for 5 hr at 90° C. The product is then extractedand purified by pouring into ice water (25 mL), made alkaline withsodium hydroxide (2N) and extracted with ether (2×10 mL). The aqueouslayer is then adjusted to pH 6.8 with hydrochloric acid (6N). Themixture is then brought to pH 7 by the addition of sodium bicarbonatesolution (5%) and extracted with chloroform (2×10 mL). The extract isdried over anhydrous sodium sulfate and evaporated in vacuo to give ayellowish solid. The crude reaction product is purified by preparativeTLC (chloroform/toluene/methanol/ammonia, 4:3:2:1, v/v).

Example 8 Preparation of(E)-2-Hydroxy-11-(3-methylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin

A mixture of(Z)-2-Hydroxy-11-(3-methylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin(2.5 mg) is dissolved in a mixture of hydrochloric acid (1 ml) andmethanol (9 ml) and heated at 140° C. (oil bath) for 4 hr. The productis isolated by means of HPLC and evaporation of solvents.

Example 9 Preparation of doxepin-N-oxide

An aqueous solution of doxepin hydrochloride was made alkaline andextracted with methylene chloride. Solvent was removed and the residue,dissolved in methanol, was treated for 5 days with an excess of 30%hydrogen peroxide. Chromatographic examination indicated that thedoxepin had been completely replaced by a more polar substancedetermined from its mass spectrum to be the N-oxide.

Hobbs, D. C., Distribution and Metabolism of Doxepin (1969) BiochemPharmacol 18:1941-1954; which is incorporated herein by reference in itsentirety.

Example 10 Preparation of (Z) doxepin-N-oxide

An aqueous solution of purified (Z)-doxepin hydrochloride is madealkaline and extracted with methylene chloride. Solvent is removed andthe residue, dissolved in methanol, is treated for 5 days with an excessof 30% hydrogen peroxide. Chromatographic examination indicates that thedoxepin has been completely replaced by a more polar substancedetermined from its mass spectrum to be the N-oxide of the (Z) isomer ofdoxepin.

Example 11 Preparation of (E)-doxepin-N-oxide

An aqueous solution of purified (E)-doxepin hydrochloride is madealkaline and extracted with methylene chloride. Solvent is removed andthe residue, dissolved in methanol, is treated for 5 days with an excessof 30% hydrogen peroxide. Chromatographic examination indicates that thedoxepin has been completely replaced by a more polar substancedetermined from its mass spectrum to be the N-oxide of the (E) isomer ofdoxepin.

Example 12 Isolation of (E)-N-acetyl-N-desmethyldoxepin,(E)-N-desmethyl-N-formyldoxepin, and (E)-N-acetyldidesmethyldoxepin

(E)-N-acetyl-N-desmethyldoxepin, (E)-N-desmethyl-N-formyldoxepin, and(E)-N-acetyldidesmethyldoxepin are isolated from Cunninghamella elegans(C. elegans) as described in the incorporated materials of Moody et al.(Drug Metabolism and Disposition (1999) 27:1157-1164). Briefly, culturesof C. elegans ATCC 9245 are incubated for 48 h at 26° C. on a rotaryshaker operating at 125 rpm and then 10 mg of doxepin hydrochloride(E./Z ratio 83:16%) dissolved in 0.5 ml sterile physiological salinesolution are added. After 96 h of incubation, the contents of eachflask, are filtered through glass wool into a separatory funnel andextracted with three equal volumes of ethyl acetate. The organicextracts are dried over sodium sulfate and evaporated to dryness invacuo at 34°. The residue is dissolved in methanol and concentrated toapproximately 100 μL by evaporation for analysis by HPLC.

The extract is injected repeatedly into a semipreparative scale HPLCsystem consisting of a Beckman model 100A pump, a Waters 486 turntableUV absorbance detector, and a Shimadzu model CR601 Chromatopacintegrator. The compounds are eluted using a linear gradient of 30 to75% methanol-buffer (v/v) over 30 min at 1.0 ml/min with a 10.0×250 mmcolumn. The buffer used is 25 mM ammonium acetate, pH 7.2. Compoundswith similar retention times are pooled. NMR and mass spectral analysisconfirms the isolation of (E)-N-acetyl-N-desmethyldoxepin,(E)-N-desmethyl-N-formyldoxepin, and (E)-N-acetyldidesmethyldoxepin.

Example 13 Isolation of (Z)—N-acetyl-N-desmethyldoxepin,(Z)—N-desmethyl-N-formyldoxepin, and (Z)—N-acetyldidesmethyldoxepin

(Z)—N-acetyl-N-desmethyldoxepin, (Z)—N-desmethyl-N-formyldoxepin, and(Z)—N-acetyldidesmethyldoxepin are isolated from Cunninghamella elegans(C. elegans) as described above in Example 12 for the (E) isomers.However, unlike Example 13, the cultures are initially incubated withdoxepin enriched for the cis (Z)-isomer of doxepin at a Z/E ratio ofgreater than 85:15. NMR and mass spectral analysis confirms theisolation of (Z)—N-acetyl-N-desmethyldoxepin,(Z)—N-desmethyl-N-formyldoxepin, and (Z)—N-acetyldidesmethyldoxepin.

Example 14 Isolation of (E)- and (Z)—N-didesmethyldoxepin

(E)- and (Z)—N-didesmethyldoxepin are isolated from blood serum andcerebrospinal fluid of patients treated with doxepin according to themethods described in the incorporated materials of Deuschle et al.(Psychopharmacology (1997) 131:19-22). Briefly, blood and cerebrospinalfluid are collected from patients being treated with doxepin. Aftercentrifugation, (15000 g for 5 min), 100 μl of the samples is injecteddirectly onto a clean-up column (10.0×4.0 mm) filled with LichrospherRP-8 DIOL. Interfering plasma or CSF constituents are washed to wasteusing water containing 5% acetonitrile at a flow rate of 1.5 ml/min.After 5 min the flow is switched onto an analytical column and the drugsof interest are separated using methanol:acetonitrile:0.008M phosphatebuffer, pH 6.4 (188:578:235; V/V) for elution. NMR and mass spectralanalysis confirms the isolation of (E)-N-didesmethyldoxepin and(Z)—N-didesmethyldoxepin.

Example 15 Isolation of (E)-2-O-glucuronyldoxepin and(E)-3-O-glucuronyldoxepin

(E)-2-O-glucuronyldoxepin and (E)-3-O-glucuronyldoxepin are isolatedfrom rat bile according to the methods described in the incorporatedmaterials of Shu et al. (Drug Metabolism and Disposition(1990)-18:1096-1099). Briefly, samples of rat bile are collected fromrats for 4 hours after intraperitoneal injection with doxepinhydrochloride (28 mg/kg). The samples are chromatographed on a gradientHPLC system that consists of two solvent delivery pumps (Waters M045), asystem controller (Waters Model 720), a UV absorbance detector (WatersModel 441), and an integrator (Hewlett 3390A). Chromotography is carriedout on a column packed with Spherisorb nitrile (3 μm, 0.46×15 cm) andmaintained at 50° C. The analysis begins with an initial isocraticperiod (1 min) with 95% solvent A (water) and 5% solvent B(acetonitrile/methanol, 75:25, v/v). Thereafter, a linear gradientelution is established by increasing the proportion of solvent B from 5%to 100% from 1 to 16 min, followed by a final period (4 min) ofisocratic elution with 100% solvent B. The flow rate is 1.5 ml/min andUV absorbance is monitored at 254 nm with a sensitivity of 0.005 AUFS.NMR and mass spectral analysis confirms the isolation of(E)-2-O-glucuronyldoxepin and (E)-3-O-glucuronyldoxepin.

Example 16 Isolation of (Z)-2-O-glucuronyldoxepin and(Z)-3-O-glucuronyldoxepin

(Z)-2-O-glucuronyldoxepin and (Z)-3-O-glucuronyldoxepin are isolatedfrom rat bile according to the methods described above in Example 16with the exception that the rats are injected with doxepin enriched forthe cis (Z)-isomer of doxepin at a Z/E ratio of greater than 85:15. NMRand mass spectral analysis confirms the isolation of(Z)-2-O-glucuronyldoxepin and (Z)-3-O-glucuronyldoxepin.

Example 17 Preparation of (E)- and (Z)-doxepin N⁺-glucuronide

The quaternary ammonium-linked glucuronide of doxepin (doxepinN⁺-glucuronide) is obtained by organic synthesis as described in theincorporated materials of Luo et al. (Drug Metabolism and Disposition,(1991) 19:722-724). Briefly, the synthetic procedure involvesquaternization of commercial samples of doxepin withmethyl(2,3,4-tri-O-acetyl-1-bromo-1-deoxy-α-D-glucopyranosid)urinate,and subsequent removal of the protecting groups by treatment with sodiumhydroxide. Thus, to prepare the (Z)-isomer of doxepin N⁺-glucuronide,(Z)-doxepin is used as the starting material. To prepare the (E)-isomerof doxepin, (E)-doxepin is used as the starting material.

Example 18 Phase II Study to Evaluate Sleep Maintenance Effects of ThreeDose Levels of Doxepin Hydrochloride (HCl) Relative to Placebo inElderly Patients with Primary Insomnia

A Phase II, randomized, multi-center, double-blind, placebo-controlled,four-period crossover, dose-response study was designed to assess theeffects of doxepin (1 mg, 3 mg and 6 mg) compared with placebo inpatients aged 65 years or older with primary sleep maintenance insomnia.Patients received a single-blind placebo for two consecutive nightsduring the PSG screening period, and double-blind study drug for twoconsecutive nights during each of the four treatment periods. Followingeach study drug administration, patients had 8 continuous hours of PSGrecording in the sleep center. Patents were allowed to leave the sleepcenter during the day after each PSG assessment was complete. A 5- or12-day study drug-free interval separated each PSG assessment visit. Theduration of study participation per patient was approximately 7 to 11weeks.

Patients who qualified for study entry, based on the screening PSGassessments, were randomized to a treatment sequence using a Latinsquare design. A final study visit was performed for patients eitherafter completion of the four treatment periods or upon discontinuationfrom the study. Efficacy assessments were made at each visit and safetyassessments were performed throughout the study.

Seventy-one patients were included in the per-protocol analysis set. Themain inclusion criteria were male and/or female patients, aged 65 yearsor older, in good general health with at least a 3-month history ofDiagnostic and Statistical Manual of Mental Disorders, fourth Edition(DSM-IV)-defined primary insomnia, reporting each of the following onfour of seven nights prior to PSG screening: ≤6.5 hours of total sleeptime (TST), ≥60 min of wakefulness after sleep onset (WASO) and ≥20 minof latency to sleep onset (LSO). Additionally, patients must have metthe following entry criteria based on PSG assessments during thescreening PSG period: wake time during sleep (WTDS)≥60 min with no PSGscreening night <45 min; TST>240 min and ≤410 min on both PSG screeningnights; latency to persistent sleep (LPS)≥10 min on both PSG screeningnights, <15 periodic limb movements with arousal per hour of sleep onthe first PSG screening night, and <15 apnea/hypopneas per hour of sleepon the first PSG screening night. Doxepin HCl 1 mg, 3 mg and 6 mgcapsules, and placebo capsules, were provided as a single dose for oraladministration.

The primary efficacy assessment was WTDS. Secondary efficacy assessmentsincluded WASO, TST, SE and WTAS. All objective efficacy assessments wereperformed on Night 1 and Night 2

Efficacy analyses used the per-protocol (PP; the primary analysis set)sets. The PP analysis set included all patients who did not haveimportant protocol derivations that would likely have effected theevaluation of efficacy, and who provided WTDS data from each of the fourtreatment periods. The primary and secondary efficacy analyses werebased on the PP analysis set.

Within each treatment period, the average of the two data points wasused for analysis, if applicable. The primary efficacy variable, WTDS,as well as the secondary objective parameters, was analyzed using ananalysis of variance (ANOVA) model with terms for sequence, patientwithin sequence, treatment and period. Pairwise comparisons of eachactive treatment versus placebo were performed using Dunnett's test. Allrandomized patients who received at least one dose of double-blind studymedication were included in the safety analyses, which were based onobserved data.

Efficacy Results

Primary

WTDS exhibited a statistically significant decrease at the doxepin 1 mg(p=0.0001), 3 mg (p<0.0001) and 6 mg (p<0.0001) dose levels comparedwith placebo in the PP analysis set. The observed mean values (±SD)were: placebo 86.0 (38.15); doxepin 1 mg 70.1 (32.78); doxepin 3 mg 66.4(31.56) and doxepin 6 mg 60.2 (28.00). The results using the ITTanalysis set were consistent with those from the PP analysis set.

Secondary

The secondary PSG efficacy assessments are summarized in Table 1. WASOexhibited a statistically significant decrease at the doxepin 1 mg(p<0.0001), 3 mg (p<0.0001), and 6 mg (p<0.0001) dose levels compared toplacebo. SE exhibited statistically significant increases at all threedose levels of doxepin (1 mg, p<0.0001; 3 mg, p<0.0001; 6 mg, p<0.0001)compared to placebo. TST exhibited statistically significant increasesat all three dose levels of doxepin (1 mg, p<0.0001; 3 mg, p<0.0001; 6mg, p<0.0001) compared to placebo. WTAS exhibited a statisticallysignificant decrease at the doxepin 3 mg (p=0.0264) and 6 mg (p=0.0008)dose levels and numerically reduced at the doxepin 1 mg dose level, allcompared to placebo.

TABLE 1 Secondary PSG Efficacy Assessments: Per-Protocol Analysis SetDoxepin Doxepin Doxepin Placebo 1 mg 3 mg 6 mg Parameter Mean MeanP-value^([1]) Mean P-value^([1]) Mean P-value^([1]) Per-Protocol (N =71) SE 74.9 78.5 <0.0001 81.0 <0.0001 82.8 <0.0001 (percent) TST 359.4376.8 <0.0001 388.8 <0.0001 397.4 <0.0001 (minutes) WTAS 13.0 10.40.5546 5.9 0.0264 5.0 0.0008 (minutes) WASO 99.0 80.5 p < 0.0001 72.3 p< 0.0001 65.2 p < 0.0001 (minutes) ^([1])P-value comparing each activetreatment versus placebo using Dunnett's test

SE was also analyzed for each hour of the night. The results aresummarized in FIG. 2. Also, Table 2 summarizes the data for hours 7 and8. With the exception of the hour 1 value for 1 mg, all three doxepindoses had numerically increased SE at each hour throughout the nightcompared to placebo, with statistically significant increased SE atseveral time points in the 3 and 6 mg dose levels. At the doxepin 6 mgdose level, SE exhibited statistically significant increases at hours 2,4, 5, 6, 7 and 8. At the doxepin 3 mg dose level, SE exhibitedstatistically significant increases at hours 5, 6, 7 and 8. At thedoxepin 1 mg dose level, SE exhibited statistically significantincreases at hours 5 and 6.

TABLE 2 Sleep Efficiency for hours 7 and 8: per-protocol analysis setDoxepin Doxepin Doxepin Parameter Placebo 1 mg 3 mg 6 mg Per-Protocol (N= 71) Hour 7 SE (percent)[1] Mean 71.7 75.8 81.6 83.9 P-value[2] 0.23760.0004 <0.0001 Hour 8 SE (percent)[1] Mean 63.2 64.8 73.1 74.8P-value[2] 0.9206 0.0009 <0.0001 [1]Measurements taken from Night 1 andNight 2 were averaged. If one of the nights had a missing value, the nnon-missing value was used. [2]P-value comparing each active treatmentversus placebo.Conclusion

Doxepin 1 mg, 3 mg and 6 mg demonstrated efficacy on sleep maintenanceparameters in elderly patients (65 years of age and older) with primarysleep maintenance insomnia, which appeared to be dose-related. Efficacyin delaying premature final awakenings was also demonstrated for doxepin1 mg, 3 mg and 6 mg as evidenced by statistically significant reductionsin WTAS at the doxepin 3 mg and 6 mg dose levels and numericalreductions at the doxepin 1 mg dose level, all compared to placebo.Also, efficacy in improving fragmented sleep at hours 7 and 8 wasdemonstrated for doxepin 1 mg, 3 mg, and 6 mg as evidenced bystatistically significant increases in SE at hours 7 and 8 in thedoxepin 3 mg and 6 mg dose levels and numerical reductions at 1 mg, allcompared to placebo. All doxepin doses were well tolerated anddemonstrated an adverse effect profile similar to placebo. There were nosignificant effects observed on next-day residual sedation. Sleeparchitecture was generally preserved.

Example 19 Phase II Study to Evaluate Sleep Maintenance Effects of ThreeDose Levels of Doxepin Hydrochloride (HCl) Relative to Placebo in AdultPatients with Primary Insomnia

A Phase II, randomized, multi-center, double-blind, placebo-controlled,four-period crossover, dose-response study was designed to assess theeffects of doxepin (1 mg, 3 mg and 6 mg) compared with placebo inpatients with primary sleep maintenance insomnia.

Patients received a single-blind placebo for two consecutive nightsduring the PSG screening period, and double-blind study drug for twoconsecutive nights during each of the four treatment periods. Followingeach study drug administration, patients had 8 continuous hours of PSGrecording in the sleep center. Patents were allowed to leave the sleepcenter during the day after each PSG assessment was complete. A 5- or12-day study drug-free interval separated each PSG assessment visit.

Patients who qualified for study entry, based on the screening PSGassessments, were randomized to a treatment sequence using a Latinsquare design. A final study visit was performed for patients eitherafter completion of the four treatment periods or upon discontinuationfrom the study. Efficacy assessments were made at each visit and safetyassessments were performed throughout the study.

Sixty-one patients were included in the per-protocol analysis set. Themain inclusion criteria were male and/or female patients, aged 18 to 64years, in good general health with at least a 3-month history ofDSM-IV-defined primary insomnia, reporting each of the following on fourof seven nights prior to PSG screening: ≤6.5 hours of total sleep time(TST), ≥60 min of WASO and ≥20 min of LSO. Additionally, patients musthave met the following entry criteria based on PSG assessments duringthe screening PSG period: WTDS≥60 min with no PSG screening night <45min; TST>240 min and ≤410 min on both PSG screening nights; LPS≥10 minon both PSG screening nights, <10 periodic limb movements with arousalper hour of sleep on the first PSG screening night, and <10apnea/hypopneas per hour of sleep on the first PSG screening night.Doxepin HCl 1 mg, 3 mg and 6 mg capsules, and placebo capsules, wereprovided as a single dose for oral administration.

The primary and secondary efficacy assessments were as described abovein Example 1. All objective efficacy assessments were performed on Night1 and Night 2 of each treatment period. Statistical methods were asdescribed in Example 1.

Efficacy Results

Primary

WTDS exhibited a statistically significant decrease at the doxepin 3 mg(p<0.0001) and 6 mg (p=0.0002) dose levels compared with placebo. WTDSwas numerically, but not significantly decreased at the doxepin 1 mgdose level. The observed mean values (±SD) were: placebo 51.9 (42.25);doxepin 1 mg 43.2 (28.21); doxepin 3 mg 33.4 (21.87) and doxepin 6 mg35.3 (25.17).

Secondary

The secondary PSG efficacy assessments are summarized in Table 3. SEexhibited statistically significant increases at all three dose levelsof doxepin (1 mg, p=0.0004; 3 mg, p<0.0001; 6 mg, p<0.0001) compared toplacebo. TST exhibited statistically significant increases at all threedose levels of doxepin (1 mg, p=0.0004; 3 mg, p<0.0001; 6 mg, p<0.0001)compared to placebo. WTAS exhibited a statistically significant decreaseat the doxepin 6 mg dose level (p=0.0105) compared to placebo. There wasa numerical decrease for WTAS at the doxepin 1 mg and 3 mg dose levelscompared to placebo; these differences were not significant. WASOexhibited a statistically significant decrease at the doxepin 1 mg(0.0130), 3 mg (p<0.0001), and 6 mg (p<0.0001) dose levels compared toplacebo.

TABLE 3 Secondary PSG Efficacy Assessments: Per-Protocol Analysis SetDoxepin Doxepin Doxepin Placebo 1 mg 3 mg 6 mg Parameter Mean MeanP-value^([1]) Mean P-value^([1]) Mean P-value^([1]) Per-Protocol (N =61) SE 80.7 84.7 0.0004 86.5 <0.0001 86.9 <0.0001 (percent) TST 387.5406.5 0.0004 415.2 <0.0001 417.2 <0.0001 (minutes) WTAS 10.2 4.1 0.14215.2 0.0697 2.5 0.0105 (minutes) WASO 62.1 47.3 0.0130 38.6 <0.0001 38.8<0.0001 (minutes) ^([1])P-value comparing each active treatment versusplacebo using Dunnett's test

SE was also analyzed for each hour of the night. The results aresummarized in FIG. 3. All three doxepin doses had numerically increasedSE at each hour throughout the night compared to placebo, withstatistically significant increased SE at several time points in the 3and 6 mg dose levels. All three doxepin doses had significantlyincreased SE during the seventh and eighth hour of the night. The datafor hours 7 and 8 are summarized in Table 4.

TABLE 4 Sleep Efficiency for Hours 7 and 8: per-protocol analysis setDoxepin Doxepin Doxepin Parameter Placebo 1 mg 3 mg 6 mg Per-Protocol (N= 71) Hour 7 SE (percent)[1] Mean 79.9 88.2 89.6 90.4 P-value[2] 0.00070.0001 <0.0001 Hour 8 SE (percent)[1] Mean 74.5 84.0 85.1 85.4P-value[2] 0.0018 0.0005 0.0003 [1]Measurements taken from Night 1 andNight 2 were averaged. If one of the nights had a missing value, the non-missing value was used. [2]P-value comparing each active treatmentversus placebo.Conclusion

Doxepin 1 mg, 3 mg and 6 mg demonstrated efficacy on sleep maintenanceparameters in adult patients with primary sleep maintenance insomnia.Doxepin 1 mg, 3 mg and 6 mg demonstrated efficacy in preventing ordelaying premature final awakenings as evidenced by significantreductions in WTAS at the doxepin 6 mg dose level and numericalreductions at the doxepin 1 mg and 3 mg dose levels, all compared toplacebo. Also, efficacy in improving fragmented sleep at hours 7 and 8was demonstrated for doxepin 1 mg, 3 mg, and 6 mg as evidenced bysignificant improvement to SE at hours 7 and 8 in all three doses, allcompared to placebo. All doxepin doses were well tolerated anddemonstrated an adverse effect profile similar to placebo. There were nosignificant effects on clinically meaningful alterations observed onnext-day residual sedation and sleep architecture.

Example 20 Phase III Study to Evaluate Sleep Maintenance Effects ofDoxepin Hydrochloride (HCl) Relative to Placebo in Patients with PrimaryInsomnia

A Phase III, randomized, double-blind, placebo-controlled,parallel-group, multicenter study was performed to assess the efficacyand safety of Doxepin HCl at two dosages, 3 mg and 6 mg, in primaryinsomnia patients with sleep maintenance difficulties. Patients with a3-month history of primary insomnia, according to Diagnostic andStatistical Manual of Mental Disorders, Fourth Edition Text Revision(DSM-IV-TR)-defined primary insomnia were enrolled.

This was a randomized, double-blind, placebo-controlled, parallel-groupstudy designed to assess the efficacy and safety of two dose levels ofdoxepin, 3 mg and 6 mg, in subjects with primary insomnia and sleepmaintenance difficulties. Efficacy and safety assessments were conductedthroughout the study. Doxepin 3 mg and 6 mg capsules, and placebocapsules, were provided as a single dose for oral administration. Sleepefficiency (SE) was evaluated. Data were analyzed as randomized andbased on observed cases.

Diagnosis and Main Criteria for Inclusion

Subjects were females and males, 18 to 64 years of age inclusive, withat least a 3-month history of primary insomnia (as defined in theDiagnostic and Statistical Manual of Mental Disorders, Fourth Edition,Text Revision), who reported experiencing ≥60 minutes of Wake AfterSleep Onset (WASO), ≥20 minutes of Latency to Sleep Onset (LSO), and≤6.5 hours of Total Sleep Time (TST) on at least 4 of 7 consecutivenights prior to PSG Screening.

Criteria for Evaluation:

Primary Efficacy Variable: The primary efficacy variable was WASO onNight 1.

Additional Objective Variables: Additional efficacy variables obtainedduring each PSG recording night during the Double-blind Treatment Periodwere Wake Time During Sleep (WTDS), TST, Sleep Efficiency (SE) overall,SE by third of the night, SE by hour of the night, Latency to PersistentSleep (LPS), latency to Stage 2 sleep, Number of Awakenings After SleepOnset (NAASO), Total Wake Time (TWT), Wake Time After Sleep (WTAS), andsleep architecture (including percentage and minutes of Stage 1, 2, and3-4 sleep; percentage of rapid eye movement [REM] and non-REM sleep; andlatency to REM sleep).

Subjective Variables: Subjective efficacy variables were subjective TST(sTST), subjective WASO (sWASO), LSO, subjective NAASO (sNAASO), andsleep quality. These variables were assessed using a questionnairecompleted in the morning following each PSG recording night. Drowsiness,ability to function, and total nap time during the day were assessedusing an evening questionnaire completed on Night 2, Night 16, and Night30. Other secondary subjective efficacy variables included the 2-itemClinical Global Impressions (CGI) scale for severity and therapeuticeffect completed by a clinician; the 5-item CGI scale pertaining totherapeutic effect completed by the subject; the Insomnia Severity Index(ISI) completed by the subject; and a subjective assessment of averagenightly total sleep time following administration of the study drug athome.

A total of 229 subjects were randomized into the study (76 to placebo,77 to 3 mg, and 76 to 6 mg). These groups were comparable with respectto weight, height, gender and baseline sleep characteristics. A total of203 (89%) subjects completed the study, with comparable earlytermination rates across treatment groups.

Summary of Results:

Of the 229 randomized subjects, 203 (89%) completed the study and 26(11%) withdrew from the study. Early termination rates and baselinecharacteristics were comparable across treatment groups. The studypopulation was female (73%) and male (27%). The mean age was 44.5 years.Subjects were White (48%), Black/African American (33%), Hispanic (16%),Asian (1%), and Other (2%).

Efficacy Results:

Primary Efficacy Variable (WASO on Night 1) Using the a priori ITTAnalysis Set

Mean WASO on Night 1 was statistically significantly decreased byapproximately 25 to 30 minutes following administration of doxepin 3 mgand 6 mg compared with placebo. Additionally, the mean WASO wasstatistically significantly decreased by approximately 15 to 20 minutesin each doxepin group compared with placebo through 29 nights oftreatment. Similar results for WASO were observed for the average ofNights 1, 15, and 29 as well as for the means of the paired study nights(Nights 1 and 2; Nights 15 and 16; and Nights 29 and 30).

There were consistent, statistically significant improvements fordoxepin 3 mg and 6 mg compared to placebo in SE second third-of-nightand SE final-third-of-night. In particular, SE at hours 7 and 8 of the 8hour period of sleep surprisingly exhibited statistically significantincreases by treatment with low-dose doxepin. These results are shown inTables 5-7, respectively. The results also are graphically depicted inFIGS. 4 and 5.

TABLE 5 Key Objective Efficacy Variables on Night 1 and Night 29 PlaceboDoxepin 3 mg Doxepin 6 mg PSG Variable (N = 72) (N = 75) (N = 73) TST(minutes) Baseline 380.3 (44.70)  380.3 (46.09)  380.3 (43.09)  Night 1373.8 (72.22)  415.3 (41.65)  420.5 (37.07)  p < 0.0001 p < 0.0001 Night29 391.0 (50.50)  408.1 (52.41)  419.1 (44.98)  p = 0.0262 p = 0.0003 SEOverall (%) Baseline 79.2 (9.31)  79.2 (9.60)  79.2 (8.98)  Night 1 77.9(15.05) 86.5 (8.68)  87.6 (7.72)  p < 0.0001 p < 0.0001 Night 29 81.5(10.52) 85.0 (10.92) 87.3 (9.37)  p = 0.0262 p = 0.0003 SE in Hour 8 (%)Baseline 78.0 (18.92) 74.9 (22.87) 76.4 (21.26) Night 1 74.5 (29.15)87.8 (14.28) 88.4 (14.25) p < 0.0001 p < 0.0001 Night 29 75.4 (26.06)81.9 (20.81) 85.8 (19.66) p = 0.0524 p = 0.0034 WTAS (minutes) Baseline 5.8 (12.72)  8.5 (16.95) 5.2 (9.22) Night 1  6.4 (15.52) 0.7 (3.71) 1.1(4.60) p = 0.0002 p = 0.0030 Night 29  5.8 (15.57) 3.2 (8.42) 2.7 (9.92)p = 0.2104 p = 0.2448 LPS (minutes)¹ Baseline 38.0 (28.56) 35.9 (29.84)39.1 (34.10) Night 1 45.0 (54.91) 26.7 (23.42) 27.1 (25.42) p = 0.0110 p= 0.0018 Night 29 31.3 (35.98) 28.0 (25.99) 24.7 (21.48) p = 0.9008 p =0.9989 Data presented are mean (SD). p-value comparing each activetreatment versus placebo was determined from an ANCOVA model thatincluded main effects for treatment and center with the baseline valueas a covariate using Dunnett's test. ¹Analysis performed onlog-transformed data.Sleep EfficiencySleep Efficiency Overall

There were statistically significant increases in mean SE overall onNight 1 for the doxepin groups compared with placebo and Night 29 (3 mgand 6 mg groups). Additionally, there were statistically significantincreases in mean SE overall for the average of Nights 1, 15, and 29 foreach doxepin group compared with placebo.

TABLE 6 SE Overall at Baseline, Night 1, Night 29, and the Average ofNights 1, 15, and 29: ITT Analysis Set Placebo Doxepin 3 mg Doxepin 6 mgSleep Efficiency Overall (%) (N = 72) (N = 75) (N = 73) Baseline (Meanof Nights −6 and −5) n = 72 n = 75 n = 73 Mean (SD) 79.2 (9.31) 79.2(9.60) 79.2 (8.98) Median (Range) 80.5 (52.3-95.7) 81.4 (53.0-94.7) 79.4(56.9-94.1) Night 1 (Visit 4) n = 72 n = 75 n = 73 Mean (SD) 77.9(15.05) 86.5 (8.68) 87.6 (7.72) Median (Range) 81.1 (14.3-97.6) 89.2(54.4-97.6) 90.5 (62.9-98.4) Diff. of LS Mean (Std. Err.)  8.6 (1.46) 9.8 (1.46) 95% CI of LS Mean Diff. (5.3, 11.8) (6.6, 13.1) p-value¹ p <0.0001 p < 0.0001 Night 29 (Visit 6) n = 68 n = 68 n = 69 Mean (SD) 81.5(10.52) 85.0 (10.92) 87.3 (9.37) Median (Range) 82.6 (54.6-96.1) 88.0(27.5-97.0) 89.8 (52.4-98.4) Diff. of LS Mean (Std. Err.)  3.8 (1.52) 5.8 (1.51) 95% CI of LS Mean Diff. (0.4, 7.1) (2.5, 9.2) p-value¹ p =0.0262 p = 0.0003 Average of Nights 1, 15, and 29 n = 72 n = 75 n = 73Mean (SD) 80.2 (11.03) 85.1 (8.95) 86.9 (7.66) Median (Range) 81.1(45.0-95.8) 86.6 (50.2-97.6) 88.7 (69.1-96.7) p-value¹ p = 0.0001 p <0.0001 ¹p-value comparing each active treatment versus placebo wasdetermined from an ANCOVA model that included main effects for treatmentand center with the baseline value as a covariate using Dunnett's test.Sleep Efficiency: Final Third of the Night

Statistically significant improvements in the mean SE value from thefinal third of the night on Night 1 were observed for each doxepingroup, 3 mg and 6 mg, compared with placebo and were sustained on Night15 (3 mg and 6 mg groups) and Night 29 (6 mg group).

TABLE 7 SE Final Third of the Night at Baseline, Night 1 and Night 29:ITT Analysis Set Placebo Doxepin 3 mg Doxepin 6 mg Sleep Efficiency (%)(N = 72) (N = 75) (N = 73) SE Final Third of the Night (%) Baseline(Mean of n = 72 n = 75 n = 73 Nights −6 and −5) Mean (SD) 79.4 (13.05)80.3 (13.43) 80.7 (13.12) Night 1 (Visit 4) n = 72 n = 75 n = 73 Mean(SD) 79.8 (17.85) 88.4 (13.89) 90.6 (7.73) p-value¹ p = 0.0002 p <0.0001 Night 29 (Visit 6) n = 68 n = 68 n = 69 Mean (SD) 81.6 (14.11)86.0 (12.90) 89.1 (11.93) p-value¹ p = 0.0838 p = 0.0007 ¹p-valuecomparing each active treatment to placebo was determined from an ANCOVAmodel that included main effects for treatment and center with thebaseline value as a covariate using Dunnett's test.Sleep Efficiency by Hour of the Night

Sleep efficiency by hour of the night on Night 1, adjusted for multiplecomparisons using Dunnett's test, is displayed in FIG. 7.

Sleep efficiency by hour of the night for each doxepin group, 3 mg and 6mg, compared with placebo was improved significantly at most assessmenttimepoints on Night 1 including Hour 8 (p<0.0001).

Sleep Efficiency in Hour 8

The mean SE in Hour 8 was 87.8% and 88.4% for the doxepin 3 mg and 6 mggroups, respectively, versus 74.5% for the placebo group, as presentedin Table 8.

TABLE 8 SE in Hour 8 at Baseline, Night 1 and Night 29: ITT Analysis SetPlacebo Doxepin 3 mg Doxepin 6 mg Sleep Efficiency in Hour 8 (%) (N =72) (N = 75) (N = 73) Baseline (Mean of Nights −6 and −5) n = 72 n = 75n = 73 Mean (SD) 78.0 (18.92) 74.9 (22.87) 76.4 (21.26) Median (Range)84 (22.5-98.3) 82.5 (1.7-99.6) 84.2 (18.8-99.2) Night 1 (Visit 4) n = 72n = 75 n = 73 Mean (SD) 74.5 (29.15) 87.8 (14.28) 88.4 (14.25) Median(Range) 89.2 (0.0-100.0) 94.2 (26.7-100.0) 93.3 (30.0-100.0) Diff. of LSMean (Std. Err.) 14.1 (3.21) 14.3 (3.23) 95% CI of LS Mean Diff. (6.9,21.3) (7.2, 21.5) p-value¹ p < 0.0001 p < 0.0001 Night 29 (Visit 6) n =68 n = 68 n = 69 Mean (SD) 75.4 (26.06) 81.9 (20.81) 85.8 (19.66) Median(Range) 85.0 (0.0-100.0) 90.4 (14.2-100.0) 94.2 (0.0-100.0) Diff. of LSMean (Std. Err.)  8.0 (3.61) 11.3 (3.57) 95% CI of LS Mean Diff. (−0.1,16.0) (3.4, 19.3) p-value¹ p = 0.0524 p = 0.0034 ¹p-value comparing eachactive treatment to placebo was determined from an ANCOVA model thatincluded main effects for treatment and center with the baseline valueas a covariate using Dunnett's test.

Example 21 Phase III Study to Evaluate Sleep Maintenance Effects ofDoxepin Hydrochloride (HCl) Relative to Placebo in Patients withTransient Insomnia

A Phase III, Randomized, Double-Blind, Placebo-Controlled,Parallel-Group, Multicenter Study was conducted to assess the efficacyand safety of doxepin HCl for the treatment of transient insomnia inadult subjects.

This randomized, double-blind, placebo-controlled, parallel-group,single-dose study was designed to evaluate the effects of doxepin 6 mgin adult subjects. A laboratory adaptation model (i.e., first nighteffect) combined with a 3-hour phase advance was implemented to inducetransient insomnia in healthy adult subjects.

Diagnosis and Main Criteria for Inclusion:

Subjects were healthy females and males, 25 to 55 years of ageinclusive, with an Epworth Sleepiness Scale score ≤12 at screening, anda 3-month history of normal nightly sleep. Eligibility also wasdetermined using protocol-defined criteria based on sleep diaryinformation obtained during the 7-day period before randomization.

Criteria for Evaluation:

Primary Efficacy Variable:

The primary efficacy variable was Latency to Persistent Sleep (LPS) onNight 1.

Key Secondary Efficacy Variable:

The key secondary efficacy variable was Wake After Sleep Onset (WASO) onNight 1.

Additional Objective Variables: Additional PSG variables obtained onNight 1 were Total Sleep Time (TST); Total Wake Time (TWT) overall andby hour of the night; Sleep Efficiency (SE) overall, by third of thenight, by hour of the night, and last quarter of the night; latency toStage 2 sleep; Wake Time During Sleep (WTDS); Wake Time After Sleep(WTAS); Number of Awakenings After Sleep Onset (NAASO) overall and byhour of the night; and sleep architecture including percentages andminutes of Stage 1, 2, and 3-4 sleep, percentages and minutes of rapideye movement (REM) sleep and non-REM sleep, and latency to REM sleep.

Subjective Variables: Subjective variables, obtained from aquestionnaire completed during the morning of Day 2, were Latency toSleep Onset (LSO), subjective TST (sTST), subjective NAASO (sNAASO),subjective WASO (sWASO), and sleep quality.

Summary of Results:

All 565 randomized subjects (282 in the placebo group and 283 in thedoxepin 6 mg group) completed the study. Demographic and other baselinecharacteristics were similar between the two treatment groups. Subjectswere female (55%) and male (45%). The mean age was 35.5 years. Subjectswere White (50%), Hispanic (32%), Black/African American (15%), Asian(1%), Native Hawaiian or other Pacific Islander (<1%), and Other (1%).

Efficacy Results:

Primary and Key Secondary Objective Efficacy Variables

Administration of doxepin 6 mg resulted in statistically significantimprovements in LPS (primary efficacy variable) and WASO on Night 1 (keysecondary efficacy variable) when compared with placebo. Improvements inLPS and WASO were independent of gender and race/ethnicity.

TABLE 9 Primary and Key Secondary Objective PSG Variables on Night 1:ITT Analysis Set Placebo Doxepin 6 mg PSG Variable (N = 282) (N = 283)p-value¹ LPS (minutes) - Primary n = 282 n = 282 LS Mean (Std. Err.)32.9 (1.83) 20.0 (1.83) p < 0.0001 WASO (minutes) - Key n = 281 n = 281Secondary LS Mean (Std. Err.) 79.4 (3.11) 40.4 (3.11) p < 0.0001¹p-value for comparing treatments was determined from an ANOVA modelthat included main effects for treatment and center.Additional Secondary Objective Efficacy Variables

There were statistically significant improvements in the objectiveefficacy variables including TST, TWT, SE, latency to Stage 2 sleep,WTDS, and WTAS following administration of doxepin 6 mg when comparedwith placebo. The analyses by hour of the night for SE and TWT werestatistically significant for doxepin 6 mg compared with placebo at alltimepoints. Improvements in TWT were distributed evenly across all hoursof the night for the doxepin 6 mg group.

There were no clinically meaningful effects for doxepin 6 mg on sleeparchitecture; sleep stages were preserved compared with placebo. Minutesspent in Stage 2 and Stage 3-4 sleep were greater in the doxepin 6 mggroup than in the placebo group with no difference between treatmentgroups in minutes spent in REM sleep.

TABLE 10 Additional Objective PSG Variables on Night 1: ITT Analysis SetPlacebo Doxepin 6 mg PSG Variable n = 281 n = 281 p-value¹ WTDS(minutes) LS Mean (Std. Err.) 74.0 (3.02) 39.8 (3.02) p < 0.0001 WTAS(minutes) LS Mean (Std. Err.)  5.4 (0.90)  0.6 (0.90) p < 0.0001 TST(minutes) LS Mean (Std. Err.) 372.6 (3.58)  423.6 (3.58)  p < 0.0001SE - Overall (%) LS Mean (Std. Err.) 77.6 (0.75) 88.3 (0.75) p < 0.0001LS Mean (Std. Err.) 69.5 (1.17) 82.5 (1.17) p < 0.0001 LS Mean (Std.Err.) 81.8 (0.99) 91.2 (0.99) p < 0.0001 SE - Final Third of the Night(%) LS Mean (Std. Err.) 81.6 (1.07) 91.1 (1.07) p < 0.0001 SE - LastQuarter of the Night (%) LS Mean (Std. Err.) 81.2 (1.15) 91.7 (1.15) p <0.0001 TWT (minutes) LS Mean (Std. Err.) 107.4 (3.58)  56.4 (3.58) p <0.0001 ¹p-value comparing doxepin 6 mg treatment versus placebo wasdetermined from an ANOVA model that included main effects for treatmentand center.

Step-down Procedure for Primary and Key Secondary Efficacy Variables:Comparison of the doxepin 6 mg group to placebo with respect to LPS wasstatistically significant. Therefore, the comparison with respect toWASO was performed. Similarly, there was a statistically significantimprovement in WASO following administration of doxepin 6 mg whencompared with placebo.

Sensitivity Analyses for Primary and Key Secondary Efficacy Variables:For both sensitivity analyses for LPS and WASO, results for the doxepin6 mg group compared with placebo were statistically significant(p<0.0001) and similar to results for observed cases using the ITTanalysis set.

Subjective Efficacy Variables: There were statistically significantimprovements in all subjective efficacy variables (LSO, sTST, sWASO,sNAASO, and sleep quality) on Day 2 following administration of doxepin6 mg when compared with placebo. Conclusions:

Administration of doxepin 6 mg when compared with placebo resulted instatistically significant and clinically meaningful effects on objectivemeasures and all subjective measures used in this study to assess sleeponset, sleep maintenance, and prevention of early morning awakenings.Doxepin 6 mg was safe and well-tolerated following single-doseadministration with an AE profile comparable to placebo. Efficacy andsafety results for doxepin 6 mg compared with placebo include:

Statistically significant effects (p<0.0001) on both objective andsubjective measures of sleep onset, as assessed by LPS (primary efficacyvariable) and LSO. The LS mean for LPS was 13.0 minutes shorter for thedoxepin 6 mg group compared with the placebo group. The geometric LSmean for LSO was 23.4 minutes for the doxepin 6 mg group compared with31.7 minutes for the placebo group.

Statistically significant effects on multiple objective and subjectivemeasures of sleep maintenance, including WASO (key secondary efficacyvariable), TST, SE overall, SE by hour of the night, WTDS, TWT overall,TWT by hour of the night, sTST, and sWASO. Results for the objective andsubjective assessments were consistent, although in some instances(i.e., TST and WASO) the subjective ratings underestimated the magnitudeof effects seen with the PSG measures of the same variables.

Statistically significant improvements in preventing early morningawakenings as assessed using PSG variables, including SE in Hours 7 and8, WTAS, and SE in the last quarter of the night.

The number of awakenings and TWT were distributed evenly across thehours of the night for doxepin after Hour 1.

No clinically meaningful effects on sleep architecture; sleep stageswere preserved.

No clinically meaningful next day hangover/residual effects.

There were no reports of potentially anticholinergic AEs or memoryimpairment-associated AEs in the doxepin 6 mg group.

There were no clinically meaningful mean changes noted in laboratorytest values, vital sign measurements, ECGs, physical examinations, orneurological assessments. There was a low incidence of AEs associatedwith laboratory values in both treatment groups.

Sleep Efficiency

Sleep Efficiency—Overall

There was a statistically significant improvement in the mean SE(overall) for the doxepin 6 mg group compared with the placebo group.The LS mean SE was greater (improved) for the doxepin 6 mg group by10.6% compared with the placebo group. The SE results are shown in Table11.

TABLE 11 SE Overall and by First, Second, and Final Third of the Nighton Night 1: ITT Analysis Set Placebo Doxepin 6 mg SE Variable (N = 282)(N = 283) SE - Overall (%) n = 281 n = 281 Mean (SD) 77.9 (14.47) 88.6(8.32) Median (Range) 80.6 (18.2-98.3) 91.0 (35.0-99.3) LS Mean (Std.Err.) 77.6 (0.75) 88.3 (0.75) Difference of LS Mean (Std. Err.) 10.6(0.99) 95% CI of LS Mean Difference (8.7, 12.6) p-value¹ p < 0.0001 95%CI of LS Mean Difference (6.8, 12.0) p-value¹ p < 0.0001 SE - FinalThird of the Night (%) n = 281 n = 281 Mean (SD) 81.7 (22.02) 91.2(9.48) Median (Range) 91.9 (1.6-100.0) 94.1 (29.4-100.0) LS Mean (Std.Err.) 81.6 (1.07) 91.1 (1.07) Difference of LS Mean (Std. Err.)  9.5(1.43) 95% CI of LS Mean Difference (6.7, 12.3) p-value¹ p < 0.0001¹p-value for comparing treatments was determined from an ANOVA modelthat included main effects for treatment and center.Sleep Efficiency—Final Third of the Night

There was a statistically significant improvement in mean SE for thefinal third of the night for the doxepin 6 mg group compared withplacebo. The LS mean SE was 9.5% greater (improved) for the doxepin 6 mggroup compared with the placebo group.

Sleep Efficiency in the Last Quarter of the Night

A summary of SE in the last quarter of the night by treatment groupusing the ITT analysis set is presented in Table 12.

There was a statistically significant improvement in mean SE in the lastquarter of the night for the doxepin 6 mg group compared with theplacebo group. The LS mean SE in the last quarter of the night was 10.4%greater (improved) for the doxepin 6 mg group compared with the placebogroup.

TABLE 12 SE in the Last Quarter of the Night on Night 1: ITT AnalysisSet Placebo Doxepin 6 mg SE - Last Quarter of the Night (%) (N = 282) (N= 283) Subjects n = 281 n = 281 Mean (SD) 81.0 (23.80) 91.4 (9.69)Median (Range) 92.5 (0.0-100.0) 94.6 (33.3-100.0) LS Mean (Std. Err.)81.2 (1.15) 91.7 (1.15) Difference of LS Mean (Std. Err.) 10.4 (1.53)95% CI of LS Mean Difference (7.4, 13.4) p-value¹ p < 0.0001 ¹p-valuefor comparing treatments was determined from an ANOVA model thatincluded main effects for treatment and center.Sleep Efficiency by Hour of the Night

Sleep Efficiency by hour for the doxepin 6 mg group compared withplacebo was statistically significantly improved at all timepoints(p≤0.0003). Sleep Efficiency by hour of the night on Night 1 ispresented in FIG. 6.

Sleep efficiency in Hour 7 using the ITT analysis set is presented inTable 13.

Sleep efficiency in Hour 8 using the ITT analysis set is presented inTable 14.

TABLE 13 SE in Hour 7 on Night 1: ITT Analysis Set Placebo Doxepin 6 mgSE - Hour 8 (%) (N = 282) (N = 283) Subjects n = 281 n = 281 Mean (SD)81.6 (27.47) 92.0 (12.19) Median (Range) 93.3 (0.0-100.0) 95.8(0.0-100.0) LS Mean (Std. Err.) 81.6 (1.34) 91.9 (1.34) Difference of LSMean (Std. Err.) 10.4 (1.79) 95% CI of LS Mean Difference (6.9, 13.9)p-value¹ p < 0.0001 ¹p-value for comparing treatments was determinedfrom an ANOVA model that included main effects for treatment and center.

TABLE 14 SE in Hour 8 on Night 1: ITT Analysis Set Placebo Doxepin 6 mgSE - Hour 8 (%) (N = 282) (N = 283) Subjects n = 281 n = 281 Mean (SD)80.4 (27.86) 90.9 (12.70) Median (Range) 94.2 (0.0-100.0) 95.0(10.8-100.0) LS Mean (Std. Err.) 81.0 (1.37) 91.5 (1.37) Difference ofLS Mean (Std. Err.) 10.5 (1.83) 95% CI of LS Mean Difference (6.9, 14.0)p-value¹ p < 0.0001 ¹p-value for comparing treatments was determinedfrom an ANOVA model that included main effects for treatment and center.

Many modifications and variations of the embodiments described hereinmay be made without departing from the scope, as is apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only.

We claim:
 1. A method for treating insomnia, the method comprising:administering an oral formulation comprising doxepin or apharmaceutically acceptable salt thereof to a patient having a sleepdisorder in which, for a given 8 hour period of desired sleep, thepatient has difficulty staying asleep during the final 60 minutes ofsaid period, wherein the oral formulation comprises a dosage of doxepinbetween about 1 and about 7 mg and is administered prior to bedtime. 2.The method of claim 1, wherein the oral formulation is effective toimprove the insomnia while minimizing next day residual sedation.
 3. Themethod of claim 1, wherein the oral formulation comprises one or moretablets.
 4. The method of claim 3, wherein each tablet comprises adosage of doxepin of about 3 mg.
 5. The method of claim 1, wherein theoral formulation comprises one or more capsules.
 6. The method of claim1, wherein the patient has difficulty staying asleep during the final 45minutes of said period.
 7. The method of claim 1, wherein the patienthas difficulty staying asleep during the final 30 minutes of saidperiod.
 8. The method of claim 1, wherein the dosage of doxepin is about1 mg.
 9. The method of claim 1, wherein the dosage of doxepin is about 3mg.
 10. The method of claim 1, wherein the dosage of doxepin is about 6mg.
 11. The method of claim 1, wherein the pharmaceutically acceptablesalt is doxepin hydrochloride.
 12. The method of claim 1, where in thepatient is 18 to under 65 years of age.
 13. The method of claim 12,wherein the dosage of doxepin is about 3 mg or about 6 mg.
 14. Themethod of claim 13, wherein the dosage of doxepin is about 3 mg.
 15. Themethod of claim 13, where in the dosage of doxepin is about 6 mg. 16.The method of claim 1, wherein the patient is 65 years of age or older.17. The method of claim 16, wherein the dosage of doxepin is about 3 mg.